tetano
Editor, Senior Moderator
J Virol. 2013 Aug 7. [Epub ahead of print]
Dual Myxovirus Screen Identifies a Small-Molecule Agonist of the Host Antiviral Response.
Yan D, Krumm SA, Sun A, Steinhauer DA, Luo M, Moore ML, Plemper RK.
Source
Center for Inflammation, Immunity & Infection, Georgia State University, Atlanta, GA 30303.
Abstract
Confronted with an increasing number of emerging and re-emerging viral pathogens, the identification of novel pathogen-specific and broad-spectrum antivirals has become a major developmental objective. Targeting host factors required for virus replication presents a tangible approach towards novel hits with broadened indication range. However, the identification of developable host-directed antiviral candidates remains challenging. We describe a novel screening protocol that interrogates the myxovirus host-pathogen interactome for broad-spectrum drug candidates and simultaneously probes for conventional, pathogen-directed hits. With resource-efficiency and pan-myxovirus activity as the central developmental parameters, we explored co-screening against two distinct, independently traceable myxoviruses in a single-well setting. Having identified a pair of unrelated pathogenic myxoviruses (influenza A virus and measles virus) with comparable replication kinetics, we observed unimpaired co-replication of both viruses, generated suitable firefly and renilla luciferase reporter constructs, respectively, and validated the protocol up to 384-well plate format. Combined with an independent counterscreen using a recombinant respiratory syncytial virus luciferase reporter, implementation of the protocol identified candidates with broadened anti-myxovirus profile in addition to pathogen-specific hits. Mechanistic characterization revealed a newly discovered broad-spectrum lead that does not block viral entry, but stimulates effector pathways of the innate cellular antiviral response. In summary, we provide proof-of-concept for the efficient discovery of broad-spectrum myxovirus inhibitors in parallel to para- and orthomyxovirus-specific hit candidates in a single screening campaign. The newly identified compound provides a basis for the development of a novel broad-spectrum small-molecule antiviral class.
PMID:
23926334
[PubMed - as supplied by publisher]
http://www.ncbi.nlm.nih.gov/pubmed/23926334
Dual Myxovirus Screen Identifies a Small-Molecule Agonist of the Host Antiviral Response.
Yan D, Krumm SA, Sun A, Steinhauer DA, Luo M, Moore ML, Plemper RK.
Source
Center for Inflammation, Immunity & Infection, Georgia State University, Atlanta, GA 30303.
Abstract
Confronted with an increasing number of emerging and re-emerging viral pathogens, the identification of novel pathogen-specific and broad-spectrum antivirals has become a major developmental objective. Targeting host factors required for virus replication presents a tangible approach towards novel hits with broadened indication range. However, the identification of developable host-directed antiviral candidates remains challenging. We describe a novel screening protocol that interrogates the myxovirus host-pathogen interactome for broad-spectrum drug candidates and simultaneously probes for conventional, pathogen-directed hits. With resource-efficiency and pan-myxovirus activity as the central developmental parameters, we explored co-screening against two distinct, independently traceable myxoviruses in a single-well setting. Having identified a pair of unrelated pathogenic myxoviruses (influenza A virus and measles virus) with comparable replication kinetics, we observed unimpaired co-replication of both viruses, generated suitable firefly and renilla luciferase reporter constructs, respectively, and validated the protocol up to 384-well plate format. Combined with an independent counterscreen using a recombinant respiratory syncytial virus luciferase reporter, implementation of the protocol identified candidates with broadened anti-myxovirus profile in addition to pathogen-specific hits. Mechanistic characterization revealed a newly discovered broad-spectrum lead that does not block viral entry, but stimulates effector pathways of the innate cellular antiviral response. In summary, we provide proof-of-concept for the efficient discovery of broad-spectrum myxovirus inhibitors in parallel to para- and orthomyxovirus-specific hit candidates in a single screening campaign. The newly identified compound provides a basis for the development of a novel broad-spectrum small-molecule antiviral class.
PMID:
23926334
[PubMed - as supplied by publisher]
http://www.ncbi.nlm.nih.gov/pubmed/23926334